tbuckley/cabot-search huggingface dataset:
Abstract IA020: Increased mitochondrial DNA mutation burden with age limits lung cancer
Authors: Eileen White
Journal: Cancer Research (2023)

Abstract Mitochondrial DNA (mtDNA) mutations accumulate with age and are found in some cancers. However, the relationship between cancer and mtDNA mutations, and the pathogenicity of those mutations, is not known. To address this question, we created a new mouse model of non-small cell lung cancer (NSCLC) with an increased mtDNA mutation burden. This model was generated by breeding the NSCLC mice model carrying floxed alleles of p53 and KrasG12D, with the mtDNA mutator mouse bearing a germline polymerase gamma mutation that disables proofreading function (POLGD257A) that is responsible for the accumulation of mtDNA mutations over time. The mutator mice with NSCLC had reduced tumor burden and prolonged survival after tumor induction in comparison to POLG wild type mice with NSCLC. Both tumor and normal tissue from mutator mice had elevated mtDNA mutation burden in comparison to wild type mice. The prolonged survival of POLGD257A mice with NSCLC was even more pronounced in older animals where mtDNA mutation burden was further increased. The same was true for a mouse model with a single pathogenic mtDNA mutation found in mitochondrial disease, indicating that it is not the number of mutations, but rather the disabling of mitochondrial function by mutation that causes reduced tumor growth. This suggested that elevated mtDNA mutation with age may suppress NSCLC. To address the mechanism by which accumulation of mtDNA mutations suppress tumor growth we examined metabolism and immune functions. We found that mtDNA mutations caused tumor cell metabolic dysfunction including increased glycolysis and decreased respiration with dependency of glycose and serine and glycine as carbon sources in vitro. Moreover, mtDNA mutations caused tumor dependence on serine and glycine in vivo. Thus, elevated mtDNA mutation burden with age may increase probability of suppression of mitochondrial function, resulting in specific metabolic dependencies in NSCLC. Thus, tumors with mtDNA mutation accumulation may be susceptible to therapeutic dietary restriction of serine and glycine. Citation Format: Eileen White. Increased mitochondrial DNA mutation burden with age limits lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA020.
Abstract A016: Aging-dependent emergent mechanical properties of single epithelial cells exploited for detection of breast cancer susceptibility
Authors: Stefan Hinz, Masaru Miyano, Antigoni Manousopoulou, Rosalyn W. Sayaman, Kristina Y. Aguilera, Michael E. Todhunter, Jennifer C. Lopez, Leo D. Wang, Lydia L. Sohn, Mark A. LaBarge
Journal: Cancer Research (2023)

Abstract Age is the major risk factor in most carcinomas, yet, little is known about the specific reasons aging increases cancer susceptibility. In the mammary gland, luminal epithelial cells rank high as the putative breast cancer cell of origin. Dysregulation of keratin intermediate filament proteins exemplifies a hallmark age-dependent change in luminal cells, which implicates mechanical states unique to cancer susceptible cells. We implemented mechano-node-pore sensing (mechano-NPS), a multi-parametric single-cell analysis that simultaneously measures cell diameter, resistance to compressive deformation, transverse deformation under constant strain, and recovery time after deformation. We demonstrated that the epithelial lineages, chronological ages, and stages of cancer progression of primary human mammary epithelial cells (HMEC) exhibited discrete mechanical phenotypes. We trained a machine learning model that accurately predicted the chronological age of average risk HMEC cells based exclusively on mechanical properties. Application of the model to cells from women who are germline carriers of high-risk cancer-causing mutations showed that they are mechanically old irrespective of their chronological age, suggesting that mechanical states could be a window into detection and prevention of cancer susceptible states. Indeed, this mechano-age model detected high-risk women with &amp;gt;90% accuracy. Mass spectrometry and cell-based functional assays in mammary epithelia revealed that cytoskeleton related proteins keratin 14 (KRT14) and pseudopodium enriched atypical kinase 1 (PEAK1) were key drivers of age-dependent mechanical signatures. Pharmacological and gene silencing approaches that targeted KRT14 and PEAK1 modulated the mechanical age of HMEC and, in the case of PEAK1 modulation, ablated luminal epithelial cells in an age- and lineage- dependent manner. We define an intersection between mechanical phenotypes and novel age-dependent changes in cytoskeleton-related proteins that we hypothesize can be exploited to assess an individual’s breast cancer susceptibility and provide new targets for cancer-prevention strategies. Citation Format: Stefan Hinz, Masaru Miyano, Antigoni Manousopoulou, Rosalyn W. Sayaman, Kristina Y. Aguilera, Michael E. Todhunter, Jennifer C. Lopez, Leo D. Wang, Lydia L. Sohn, Mark A. LaBarge. Aging-dependent emergent mechanical properties of single epithelial cells exploited for detection of breast cancer susceptibility [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A016.
Abstract B024: Increasing cellular longevity in budding yeast by activating the Anaphase Promoting Complex
Authors: Rachel E. Harris, Troy A. A. Harkness
Journal: Cancer Research (2023)

Abstract The Anaphase Promoting Complex (APC), a large and highly conserved ubiquitin ligase, is involved in genome stability, resistance to cancer progression, and has an important role in promoting health and lifespan. While best known for its function during the events of the cell cycle, the APC also has important roles outside of mitosis in aging cells. Understanding changes in function of the APC, and how these changes can be optimized, may increase our knowledge of cellular longevity and how it can be enhanced. We hypothesize that the APC loses function with age, and that the introduction of biological activators may aid to rescue these effects, improving the overall health of the cell to extend longevity. The abundance of orthologous genes and pathways between eukaryotes, complemented by the relative ease of genetic manipulation, allows for rapid advancement of research by deciphering gene functions in a yeast model to predict human disease and aging. By extension, increasing cell health in multicellular organisms will ultimately enhance the health of the entire organism. A dual screen was performed in the Harkness Lab on a library of short, random peptides to identify those which reproducibly interact with APC subunits, with particular interest on those which have an affect on function. Current research has found that several of these peptides are effective at extending cellular lifespan and suppressing APC mutant phenotypes, providing a novel means of exploring APC function in aging cells. Utilizing this direct biological activation of the APC, in addition to commercially available activators that function indirectly, I aim to identify potential therapeutic agents that can increase APC activity and extend lifespan utilizing Saccharomyces cerevisiae as a model organism. Citation Format: Rachel E. Harris, Troy A. A. Harkness. Increasing cellular longevity in budding yeast by activating the Anaphase Promoting Complex [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B024.
Abstract A004: Identification and characterization of the cancer permissive environment in companion dogs
Authors: Jaime F. Modiano, Ashley J. Schulte, Taylor A. DaPauw, Ali Khammanivong, Jong H. Kim, Aaron L. Sarver, Gary R. Cutter, Eric Lindquist, Kelly M. Makielski
Journal: Cancer Research (2023)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR008) of the Conference Proceedings. Citation Format: Jaime F. Modiano, Ashley J. Schulte, Taylor A. DaPauw, Ali Khammanivong, Jong H. Kim, Aaron L. Sarver, Gary R. Cutter, Eric Lindquist, Kelly M. Makielski. Identification and characterization of the cancer permissive environment in companion dogs [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A004.
Abstract IA017: An oncogenic histone reader promotes metaplastic TNBC
Authors: Vrutant V. Shah, Shucheng Miao, Patrick M. Krause, Sabrina A. Stratton, Lalit R. Patel, Michelle C. Barton
Journal: Cancer Research (2023)

Abstract Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) led to spontaneous development of mammary carcinosarcoma tumors, lacking ER, PR and HER2, comprising 70% of all mammary tumors that developed with 40% penetrance. We saw strong correlation of Trim24COE carcinosarcoma tumors with human MpBC tumors and derived a conserved Trim24COE gene signature of Glycolysis, EMT and mTORC1 signaling pathways. Global and single-cell tumor profiling revealed Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. To assess TRIM24-dependent metabolic alterations, we developed Trim24COE carcinosarcoma spheroid cultures. Tumor-derived Trim24COE carcinosarcoma spheroids exhibit TRIM24-dependent EMT and repressed cellular and mitochondrial ROS levels. We found that TRIM24 expression increased c-myc, NADPH and NRF2 levels to drive ROS repression and TRIM24-dependent cell survival under oxidative stress. TRIM24 mediates NRF2 activation at the level of chromatin structure activation, as shown by ATAC-seq of Trim24COE and shTrim24 carcinosarcoma spheroids. These in vivo and ex vivo models of metaplastic TNBC offer a platform for mechanistic discovery and nomination of potential therapeutic avenues for this highly malignant TNBC subtype. Citation Format: Vrutant V. Shah, Shucheng Miao, Patrick M. Krause, Sabrina A. Stratton, Lalit R. Patel, Michelle C. Barton. An oncogenic histone reader promotes metaplastic TNBC [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA017.
Abstract A023: Analysis of survival and prognostic factors for patients with non-small cell lung cancer and brain metastasis: 10-year experience in a single institution
Authors: Seung Ho Yang
Journal: Cancer Research (2023)

Abstract The aims of the study were 1) to perform the review of non-small cell lung cancer (NSCLC) patients with brain metastasis in our institution, 2) to investigate the response and prognostic factor of brain metastasis after institution’s best treatment, and 3) to suggest the shift of treatment paradigms for brain metastasis. From Jan. 2007 to Oct. 2018, A total 214 NSCLC patients with brain metastasis were enrolled. Female to male ratio was 0.65 and median age at diagnosis of NSCLC was 64 years (range, 30-90). 54 patients had a solitary brain metastasis and 76 patients had more than 10 lesions. Supratentorial, infratentorial and both locations were 106, 17, and 91 patients, respectively. 116 patients (54%) had symptoms associated with brain metastasis at the diagnosis of brain metastasis. Radiation only, radiosurgery, craniotomy with whole brain radiotherapy (WBRT), and supportive care were given for brain metastasis in 111 (52%), 10 (5%), 13 (6%) and 61 (29%) patients, respectively. Overall survival (OS) was associated with age, treatment modality, histology, egfr mutation. Median OS of Radiation only, radiosurgery, craniotomy with WBRT, and supportive care was 13, 15, 15 and 9 months, respectively (P-value 0.044). Median OS of adenocarcinoma and squamous cell carcinoma was 15 and 4 months, respectively (P-value &amp;lt;0.05). Median OS of egfr mutation and wild type was 18 and 9 months, respectively (P-value 0.016). The number and location of brain metastasis, symptoms and sex were not associated with OS Serial brain imaging was performed in 99 patients. 61 out of them (62%) developed shrinkage of brain metastasis (response group). Median OS of response and non-response group were 23 and 17 months (p-value 0.618). Age is significantly associated with response of brain metastasis to the institution’s best treatment (p-value 0.047). Interestingly, 3 patients developed complete remission of brain metastasis following WBRT and chemotherapy. The response duration was 431, 390, 641 days, respectively. Our data show that the prognosis of brain metastasis primarily depends on the age of NSCLC patients rather than the number, location of brain metastasis, treatment modality. Survival of NSCLC patients with brain metastasis was about 15 months despite the institution’s best treatment. The authors suggest that we should update our institution’s treatment policy and provide the latest treatments for patients. Citation Format: Seung Ho Yang. Analysis of survival and prognostic factors for patients with non-small cell lung cancer and brain metastasis: 10-year experience in a single institution [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A023.
Abstract IA012: Age related changes in the tumor microenvironment drive tumor progression
Authors: Sheila A. Stewart
Journal: Cancer Research (2023)

Abstract The stromal compartment plays a pivotal role in tumor progression. This is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells and its expression levels correlate with poor prognosis. Using clinically relevant breast cancer metastasis models, we show that orally administered, small-molecule inhibitors of p38MAPKα or its downstream kinase, MK2, each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. Further we found that this effect is mediated by inhibition of the p38MAPKα pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, we also found that these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity for cancer patients that drastically impacts their quality of life. Mechanistic studies revealed that p38MAPKα’s ability to limit tumor growth within the bone is dependent on CD4 T cells and macrophages. To determine which cell types within the bone contribute to tumor growth and bone loss, we carried out single cell RNA-sequencing of stromal cells located within the bone metastatic lesion and cells outside the lesion. We found numerous differences that could explain how the stromal compartment contributes to tumor progression and bone loss and how inhibition of p38MAPKα or MK2 contribute. These data underscore the vital role stromal-derived factors play in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss. Citation Format: Sheila A. Stewart. Age related changes in the tumor microenvironment drive tumor progression [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA012.
Abstract B020: Pre-malignant plasma cells exhibit a senescence-like phenotype and accumulation of transposable elements
Authors: Gabriel Alvares Borges, Angelo Jose Guilatco, Christine M. Hachfeld, Ming Ruan, Sonya Royzenblat, Ming Xu, Claire M. Edwards, Marta Diaz-delCastillo, Thomas L. Andersen, Taxiarchis Kourelis, Tamar Tchkonia, James L. Kirkland, Matthew T. Drake, Megan Weivoda
Journal: Cancer Research (2023)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR012) of the Conference Proceedings. Citation Format: Gabriel Alvares Borges, Angelo Jose Guilatco, Christine M. Hachfeld, Ming Ruan, Sonya Royzenblat, Ming Xu, Claire M. Edwards, Marta Diaz-delCastillo, Thomas L. Andersen, Taxiarchis Kourelis, Tamar Tchkonia, James L. Kirkland, Matthew T. Drake, Megan Weivoda. Pre-malignant plasma cells exhibit a senescence-like phenotype and accumulation of transposable elements [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B020.
Abstract A018: Abiraterone vs. enzalutamide: Does age impact one treatment over another
Authors: Nikita Nikita, Amy Shaver, Krupa Gandhi, Scott W. Keith, Swapnil Sharma, Grace Lu-Yao
Journal: Cancer Research (2023)

Abstract Background: Abiraterone and Enzalutamide are two of the most commonly used treatments for prostate cancer (PCa). Currently, both these medications are approved for similar clinical indications even though they have different toxicity profiles. This study aims to identify if patients and providers prefer one medication to another and if the choice depends on age. Methods: We used SEER-Medicare data to identify primary PCa patients diagnosed between 1999 and 2017. We excluded those diagnosed at death. Abiraterone and enzalutamide use was identified using part D files. Patients had 6 months continuous part D coverage prior to treatment. Age was parameterized categorically: 65-74 years, 75-84 years, and over 85 years. Descriptive statistics were generated and evaluated by Chi-square tests for all categorical variables. Multivariable logistic regression was used to investigate disparities between the treatments adjusting for demographic characteristics. Results: We identified 8,398 patients with PCa over 65 years of age; 4,180 used abiraterone and 4,218 used enzalutamide. The demographic characteristics for both groups were similar (p = 0.1557). Most patients were 65-74 years old (62.6% in the abiraterone group and 62.4% in the enzalutamide group), followed by approximately 30% of each group in the 75-84 age range. Finally, the enzalutamide group had 8.2% 85 years and older, while the abiraterone group had 7.1%. The appeared to be no preference in odds of use of either medication by age group. When comparing the very old (85+) to the 65-74 year olds (OR=0.906; 95% CI 0.745, 1.101; p=0.3727). Nor was there a statistical significance when comparing odds of use between 75-84-year-olds to those who were 65-74 (OR=0.978; 95%CI 0.873, 1.095; p=0.6927). Conclusion: Our study found that abiraterone and enzalutamide use among patients does not differ substantially by age groups. Further studies are warranted to understand these associations better. Citation Format: Nikita Nikita, Amy Shaver, Krupa Gandhi, Scott W. Keith, Swapnil Sharma, Grace Lu-Yao. Abiraterone vs. enzalutamide: Does age impact one treatment over another [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A018.
Abstract IA006: Measuring the microbiome: Improving the predictive power of microbiome analysis in cancer outcomes
Authors: Ami S. Bhatt
Journal: Cancer Research (2023)

Abstract More than 1,000 species of bacteria, archaea, viruses and fungi live in the human gut. Far from being passive passengers, these organisms strongly interact with one another and with their host’s metabolism and immune system. Compelling early experiments have demonstrated associations between the intestinal microbiome composition and obesity, cardiovascular diseases, and certain cancer chemotherapies’ efficacy. Yet teasing apart the mechanisms by which microbes impact host health has been challenging. To accelerate an otherwise challenging, slow and tedious process and to deconstruct mechanisms, we must critically examine our existing “tool kit” for studying the microbiome, and mature our measurement tools to meet these challenges. Our translational laboratory builds and designs observational and interventional clinical cohorts to study. We have also steadfastly worked to develop genomic tools to study strain level dynamics of the microbiome, how microbial genomes change over time and how microbes use hidden “microproteins” to communicate with each other and their human hosts. In this presentation, I will speak about three recent developments in our lab: (1) I will introduce the importance of absolute quantification in microbiome research, and our efforts toward that. This will form the basis of revised estimates of the number of microbial cells in a human body. (2) I will give an overview of a new computational workflow called “Phanta”, which enables simultaneous taxonomic profiling of eukaryotes, bacteria and viruses in a human gut metagenomic sample. (3) I will share unpublished work on how antibiotic exposure negatively impacts cancer outcomes in patients with triple-negative breast cancer. Citation Format: Ami S. Bhatt. Measuring the microbiome: Improving the predictive power of microbiome analysis in cancer outcomes [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA006.